This Article Extract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kishimoto, C. Articles by Feldman, A. M. Search for Related Content PubMed PubMed Citation Articles by Kishimoto, C. Articles by Feldman, A. M. Pubmed/NCBI databases Substance via MeSH Medline Plus Health Information Cardiomyopathy Related Collections Cardiovascular Pharmacology Myocardial cardiomyopathy disease

(Circulation. 1999;99:975-978.)
© 1999 American Heart Association, Inc.

Correspondence

Intravenous IgG: Supertherapy for Myocarditis and Acute Dilated Cardiomyopathy

C. Kishimoto; H. Takada; Y. Hiraoka

Toyama Medical and Pharmaceutical University, Toyama, Japan

To the Editor:

We read with great interest the article by McNamara et al¹ on intravenous immunoglobulin (IgG) therapy for myocarditis and acute dilated cardiomyopathy (DCM). There is as yet no general agreement of effective treatment of myocarditis and acute DCM. These workers are to be congratulated for conducting a well-designed clinical study of adult patients with NYHA class III to IV heart failure, based on previously published clinical² and experimental³ experience. We would like to stress 3 points that we consider crucial in our understanding of the significance of this treatment.

The first is related to the presence of preceding or associated infectious manifestations (ie, fever, pleurodynia, myalgia, and upper respiratory tract symptoms). This strongly suggests that myocarditis is of viral or infectious origin. Accordingly, as shown in our previous study,³ intravenous polyclonal IgG used in the study by McNamara et al¹ could have neutralizing antibody activities against causative agents. In this case, the effects of IgG may be drastic and super, as shown in the early study in our article.³

The second point deals with the potential histological improvement by this treatment, even in the later stage, as shown in our study.³ We consider that the marked and super improvement of left ventricular ejection fraction seen in all the patients in the study¹ may correlate with and depend on histological improvement. Some additional pathological data (ie, serial endomyocardial biopsy) could serve to make readers more clearly understand this point.

Finally, although the precise mechanisms responsible for the efficacy of this treatment are still unknown,^{4 5} IgG therapy is considered to have immunomodulatory and anti-inflammatory effects, as shown in our study.³ The former includes anti-idiotype, anti-autoantibody properties, and reticuloendothelial system blockade; the latter, downregulation of inflammatory cytokines, a sump for activated complement, and anti-superantigen antibodies. Thus, we keenly agree with the proposal that a more widespread randomized, placebo-controlled clinical trial in a larger population of patients with myocarditis and acute as well as chronic (ongoing) DCM⁶ is warranted.

References

1. McNamara DM, Rosenblum WD, Janosko KM, Trost MK, Villaneuva FS, Demetris AJ, Murali S, Feldman AM. Intravenous immune globulin in the therapy of myocarditis and acute cardiomyopathy. Circulation. 1997;95:2476–2478.[Abstract/Free Full Text]
   
2. Drucker NA, Colan SD, Lewis AB, Beiser AS, Wessel DL, Takahashi M, Baker AL, Perez-Atayde AR, Newburger JW. Gamma-globulin treatment of acute myocarditis in the pediatric population. Circulation. 1994;89:252–257.[Abstract/Free Full Text]
   
3. Takada H, Kishimoto C, Hiraoka Y. Therapy with immunoglobulin suppresses myocarditis in a murine coxsackievirus B3 model: antiviral and anti-inflammatory effects. Circulation. 1995;92:1604–1611.[Abstract/Free Full Text]
   
4. Wolf HM, Eibl MM. Immunomodulatory effect of immunoglobulins. Clin Exp Rheum. 1996;14(suppl 15):S17–S25.
   
5. Rosen FS. Putative mechanisms of the effect of intravenous -globulin. Clin Immunol Immunopathol. 1993;67:S41–S43.[Medline] [Order article via Infotrieve]
   
6. Richardson P, McKenna W, Bristow M, Maisch B, Mautner B, O'Connell J, Olsen E, Thiene G, Goodwin J, Gyarfas I, Martin I, Nordet P. Report of the World Health Organization/International Society of Federation of Cardiology Task Force on the Definition and Classification of Cardiomyopathies. Circulation. 1996;93:841–842.[Free Full Text]
   

Response

Dennis M. McNamara, MD

Assistant Professor of Medicine Director, Cardiomyopathy Clinic

Arthur M. Feldman, MD, PhD

Professor of Medicine Chief, Division of Cardiology, University of Pittsburgh Medical Center, Pittsburgh, Pa

Drs Kishimoto, Takada, and Hiraoka have raised several excellent points about the potential therapeutic use of immune globulin. First, we agree that patients presenting early in the viremic stage of myocarditis, as suggested by fever and other clinical symptoms, may achieve the greatest benefit from immune globulin therapy, in part because of its antiviral activity. The benefit of early therapy is supported not only by work in murine models but also by previous work in the most extensive cardiac disorder studied to date, Kawasaki Disease.

The challenge in designing therapeutic interventions in dilated cardiomyopathy is that most adults present long after the presumed viremic phase of the illness, have no systemic inflammatory symptoms, and have a negative endomyocardial biopsy. Importantly, in our study, this group of patients also appeared to benefit from immune globulin, and this more likely resulted from the immune modulatory properties of high-dose intravenous therapy. Whether this reflects its anti-idiotype effects or direct effects on inflammatory mediators such as tumor necrosis factor or other cytokines remains to be determined. We are pursuing studies involving sequential endomyocardial biopsy to evaluate whether changes in tissue cytokine expression correlate with recovery of function.

Though we are encouraged by the improvements seen in this published series of patients, a larger controlled trial is needed to evaluate this potential therapy. A randomized, placebo-controlled, multicenter study of Intervention in Myocarditis and Acute Cardiomyopathy with intravenous immunoglobulin (the IMAC trial) has recently completed the enrollment phase at 6 US centers. Outcome data will be available in the spring of 1999 and will more clearly determine whether immune globulin is an important addition to current therapies of myocarditis and acute cardiomyopathy.

This article has been cited by other articles:

				C. Kishimoto, H. Takada, H. Kawamata, M. Umatake, and H. Ochiai Immunoglobulin Treatment Prevents Congestive Heart Failure in Murine Encephalomyocarditis Viral Myocarditis Associated with Reduction of Inflammatory Cytokines J. Pharmacol. Exp. Ther., November 1, 2001; 299(2): 645 - 651. [Abstract] [Full Text] [PDF]

This Article Extract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kishimoto, C. Articles by Feldman, A. M. Search for Related Content PubMed PubMed Citation Articles by Kishimoto, C. Articles by Feldman, A. M. Pubmed/NCBI databases Substance via MeSH Medline Plus Health Information Cardiomyopathy Related Collections Cardiovascular Pharmacology Myocardial cardiomyopathy disease